Neurodegeneration generally refers to the loss of structure or function of neurons, impairment of normal neuronal functions, and includes the death of neurons. Neurodegeneration results from various different causes including genetic mutation, mitochondrial dysfunction, and the inability to handle increasing levels of oxidative or nitrosative stress can also lead to the progression of neurodegeneration (67). Substantial evidence from many in vitro and in vivo studies suggests that there is a commonality of events for the progression of many neurodegenerative diseases of aging. Some of these neurodegenerative diseases include Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), and among the most common of the neurodegenerative disorders is Alzheimer's disease (AD). AD is a progressive and irreversible burden on patients, caregivers, and society (68). Mounting evidence in AD as well as in most neurodegenerative diseases shows an association with oxidative and nitrosative stress. Nitrosative stress and cell damage results when reactive nitrogen species (RNS) act together with reactive oxygen species (ROS).
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed during normal metabolism but an imbalance may result from the increase production of free radicals or from the failure of antioxidants and antioxidant enzymes to adequately scavenge the damaging molecules. This imbalance has been documented to be involved in AD (69). Several studies provide clear evidence that RNS, in particular peroxynitrite (ONOO−) formation, contributes to the pathologies of chronic neurodegenerative diseases such as AD, Parkinson's disease, multiple sclerosis, and Amyotrophic lateral sclerosis (4). Peroxynitrite is formed from the reaction of nitric oxide radical (NO·) with superoxide (O2·−). Mitochondrial injury seems to be a primary cause of ONOO− promoting neurotoxic effects (5, 6). Widespread ONOO− mediated damage is seen in brain tissue from AD in the form of increased protein nitration in neurons (7).
The administration of antioxidants and antioxidant enzymes to treat diseases due to increased ROS and RNS in human clinical trials have heretofore been less than satisfactory due to issues with bioavailability and stability after administration.
To answer this need, synthetic catalytic scavengers of ROS and RNS have been made and tested in various model systems. Copious metalloporphyrins have been synthesized to have high reactivity with, O2·−, H2O2, NO· and ONOO− (14-17). Most studies affirm metalloporphyrins are useful tools for research and understanding the roles that ROS and RNS may play in diseases, however, their potential toxicity due to metals has often come into question for their use in humans.
Neurons have a high energy demand and contain several hundred mitochondria per cell and therefore have increased exposure to ROS and RNS. Mitochondria are a primary site of the intercellular formation of ONOO− (12) and mitochondrial dysfunction has been shown to contribute to disease or neuronal death (13). The ability to scavenge ONOO− is a critical therapeutic intercession in degenerative diseases associated the overproduction or unbalanced production of O2·− and NO· and thus, ONOO−.
To maintain their energy producing function, mitochondria must frequently divide and fuse. Evidence suggests that an imbalance in mitochondrial division and fusion plays a causal role in AD (78). Mitochondrial division and fusion is regulated by large GTPases of the dynamin family. Dynamin-related protein 1 (DRP1) is required for mitochondrial division. Inhibition of mitochondrial division by expression of the GTPase defective DRP1K38A mutant provides protection against excessive NO, NMDA, or Aβ (5). The exact mechanism that accounts for the NO-induced mitochondrial fragmentation remains unclear. A recent report suggested that S-nitrosylation of DRP1 at cysteine 644 increases DRP1 activity and is the cause for the peroxynitrite-induced mitochondrial fragmentation in AD (85, 50). However, the work remains controversial, suggesting alternative pathways might be implicated (85, 86). Nitrosative stress causes rapid DRP1 Serine 616 (S616) phosphorylation, which promotes its translocation to mitochondria and organelle division (86, 87). In mitotic cells DRP1 5616 phosphorylation is mediated by Cdk1/cyclinB1 and synchronizes mitochondrial division with cell division (88, 89). Interestingly, p-DRP1 S616 levels are markedly increased in brains of individuals with AD, suggesting that this event might contribute to the change in mitochondrial morphology and energy metabolism in AD (86, 88). The kinase responsible for DRP1 5616 hyperphosphorylation in AD is unknown, but Cdk5/p25 is a potential candidate kinase mediating this process (7, 90). Notably, aberrant Cdk5/p25 signaling causes tau hyperphosphorylation in postmitotic neurons and is implicated in Aβ-mediated neurodegeneration (88, 91-93).